Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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Severa Bunda1, Kelly Burrell2, Pardeep Heir1

  • 1Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, M5S1A8 Ontario, Canada.

Nature Communications
|December 1, 2015
PubMed

Insights

SHP2 dephosphorylates Ras, activating Ras/ERK/MAPK signaling and promoting cancer growth. Inhibiting SHP2 reduces glioblastoma growth and progression, identifying SHP2 as a therapeutic target for Ras-driven cancers.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Ras phosphorylation by Src kinase inhibits Raf binding and promotes GTP hydrolysis.
  • Understanding Ras regulation is crucial for cancer therapy.

Purpose of the Study:

  • To identify the tyrosine phosphatase responsible for Ras dephosphorylation.
  • To investigate the role of SHP2 in Ras signaling and glioblastoma.

Main Methods:

  • Biochemical assays to identify SHP2 as the Ras-dephosphorylating phosphatase.
  • Analysis of SHP2 activity in glioma cell lines and patient samples.
  • Pharmacological inhibition of SHP2 in preclinical cancer models.

Main Results:

  • SHP2 dephosphorylates Ras, enhancing Raf association and Ras/ERK/MAPK pathway activation.
  • Elevated SHP2 activity observed in glioblastoma multiforme (GBM) and glioma.
  • SHP2 inhibition reduced GBM proliferation, colony formation, and tumor growth in vivo.
  • SHP2 inhibition decelerated astrocytoma progression to GBM in a mouse model.

Conclusions:

  • SHP2 is a direct activator of Ras and a key regulator of Ras/ERK/MAPK signaling.
  • SHP2 is a potential therapeutic target for cancers with oncogenic or hyperactive Ras.
  • Targeting SHP2 offers a strategy against previously 'undruggable' Ras-driven tumors.

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